The present invention relates generally to processes for isomerization of maleic acid and monoesters and monoamides thereof to the corresponding fumaryl forms.
These fumaryl monoamides and monoesters may be aminated either enzymatically or through microbial fermentation to yield either aspartame (APM) from fumaryl-phenylalanine methyl ester or aspartyl phenylalanine (AP) from fumaryl-phenylalanine. Monobenzyl fumarate could also then be aminated to yield beta-benzyl aspartate which is a useful intermediate in several synthetic pathways for aspartame, but is difficult to prepare by purely chemical means.
Numerous methods have been disclosed for catalytic inversion of maleic acid to fumaric acid according to the following scheme. ##STR1##
As an early example, Terry and Eichelberger, Journal of the American Chemical Society 47, pp. 1402-1412 (1925) discloses use of hydrobromic acid, hydrochloric acid and potassium thiocyanate catalysts in aqueous solution to isomerize maleic acid to fumaric acid. This procedure, however, has been observed to be without merit as a method of isomerization of maleyl amides and esters due to the fact that amide and ester bonds are easily hydrolyzed under the recommended isomerization conditions. Nozaki and Ogg, J. Am. Chem. Soc. 63, pp 2583-2586 (1941) disclose studies suggesting a mechanism involving both a cation and anion for acid-catalyzed isomerization of maleic acid to fumaric acid in aqueous solution.
Spatz, U.S. Pat. No. 2,548,687 discloses the conversion of maleic acid to fumaric acid catalyzed by mono-, di- and tri-substituted thioureas in heated aqueous solution yielding a 65% recovery of the fumaryl compound. The inventors subsequently disclosed use of this method to isomerize the monomethyl ester of maleic acid to methyl fumarate but note, however, the maleyl monoethyl ester fails to undergo conversion under such conditions. Spatz and Stone, J. Org. Chem. 23, p 1559-1560 (1958).
Thomas. U.S. Pat. No. 3,953,616 discloses a method for preparation of fumarate monoesters from maleate monoesters employing magnesium bromide as a catalyst.
Clemo and Graham, J. Chem. Soc., pp 213-216 (1930), discloses that certain organic bases can serve to assist transformation of methyl maleate to crystalline methyl fumarate. Organic bases noted to be useful for this process include piperidine, dimethylamine, diethylamine, piperazine, methylamine, allylamine, benzylamine, phenylethylamine, and aniline.
Dymicky and Buchanan, Org. Prep. Proc. Intern. 17, No. 2, pp. 121-131 (1985) discloses isomerization of maleyl monoalkyl ester compounds to the corresponding fumaryl monoalkylester compounds. Reaction conditions include elevated temperatures using a fumaryl chloride catalyst to isomerize monoalkyl maleate to monoalkyl fumerate. The alkyl esters contain from one to eighteen single-chained carbon atoms.
British Patent Specification No. 1246349 discloses a method of isomerization of maleyl ester and amide compounds to fumaryl ester and amide compounds in inert aprotic solutions of N,N-dimethyl formamide, hexamethyl phosphoramide, pyridine N-oxide and N,N-dimethyl-O,O'-diethyl phosphoramidate.
German Patent No. DE 3444915-A1 discloses the preparation of fumaryl phenylalanine from maleyl phenylalanine and also describes the use of fumaryl phenylalanine to prepare L-aspartyl L-phenylalanine alkyl esters. No details as to specific methods of preparation are claimed; however, a method is specified as disclosed in the aforementioned British Patent No. 1246349.
Arivoshi, Japanese Patent No. 74,42,491 discloses synthesis of aspartame in a two step process. Alkyl esters of phenylalanine are treated with fumaryl chloride in organic solvent at 0.degree.-60.degree. C. to give chlorofumaryl phenylalanine alkyl esters which when hydrolyzed yield the fumaryl phenylalanine alkyl esters. Amination of these compounds yields aspartyl Phenylalanine alkyl esters which are useful as artificial sweeteners.
Also of interest to the background of the present invention are J. Med. Chem. 18, No. 10, pp 1004-1010 (1975) disclosing the maleic amide of L-phenylalanine (Mal Phe); and the Japanese Kokai Patent No. 73 52,741 disclosing the maleic amide of the methyl ester of L-phenylalanine (Mal PM).
A need continues to exist in the art for improved methods for production of fumaryl compounds (e.g., fumaric acid and monoesters and amides thereof) from the corresponding maleyl compounds which are both efficient and economic and lend themselves to large scale commercial uses.